Carcinogenesis Advance Access published online on October 10, 2003
Carcinogenesis, doi:10.1093/carcin/bgg173
© 2003 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755
* Corresponding author. E-mail: Bill.D.Roebuck{at}Dartmouth.edu.
Received 27 May 2003
; revised 28 August 2003
; accepted 10 September 2003
Oltipraz and related dithiolethiones constitute an important class of chemopreventive agents that enhance the expression of carcinogen detoxication and antioxidant genes. Dose-response studies were undertaken to characterize the cancer chemopreventive activities of several dithiolethiones that are at least as active as oltipraz as inducers. Inhibition of formation of preneoplastic lesions and formation of DNA adducts in livers of rats exposed to aflatoxin B1 (AFB1) was monitored. In the tumorigenesis experiment, the dithiolethiones were orally gavaged 3 day/week for 3 successive weeks and at 4 doses ranging from 0.03 to 0.3 mmol/kg body weight. AFB1 was gavaged beginning one week after the start of the dithiolethiones and for two successive weeks. The burden of AFB1-induced putative preneoplastic lesions (GST-P positive foci) was quantified by light microscopy. Reduction in AFB-DNA adduct burden was assessed 24 hours following the first dose of AFB1. Both the parent 1,2-dithiole-3-thione (D3T) and its 5-tert-butyl derivative were more potent inhibitors than oltipraz against these endpoints, while two of the seven tested analogs were slightly less inhibitory. D3T, the most potent dithiolethione of this series, was examined by microarray analysis for induction of hepatic genes at an intermediate chemopreventive dose (0.1 mmol/kg). Transcript levels of eight genes, including two known to detoxify aflatoxin, namely, glutathione S-transferase A5 (GSTA5) and aflatoxin B1 aldehyde reductase (AFAR) were elevated. Western analysis indicated that induction of hepatic GSTA5 and AFAR were directly related to the dose of D3T. At the highest dose of D3T (0.3 mmol/kg), protein levels of GSTA5 and AFAR were induced by 7- and 27-fold, respectively. While efficacy in humans has yet to be tested, D3T is clearly more potent than oltipraz and serves as a useful molecular probe for determining the key events associated with protection by this class of agents.
Evaluation of the cancer chemopreventive potency of dithiolethione analogs of oltipraz
2 Department of Pathology, Dartmouth Medical School, Hanover, NH 03755
3 Department of Pathology, Guangxi Cancer Institute, Nanning, 530027, People's Republic of China
4 W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, TN 38152
5 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
6 Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205
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